This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was conducted as post-approval commitments to the FDA and other regulatory agencies to confirm the efficacy and safety of sunitinib in advanced and/or metastatic, well-differentiated, unresectable pNETs.

1. Presented at the 14th Annual European Neuroendocrine Tumor Society (ENETS) Conference, March 8–10, 2017, Barcelona, Spain
CONCLUSIONS
OO Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5%
(95% CI, 16.7–33.8) observed in this phase IV trial support the
outcomes of the pivotal phase III trial of sunitinib in pNETs and
confirm its activity in this setting.
OO OS data were not mature at the time of the primary analysis.
OO AEs were consistent with the known safety profile of sunitinib.
OO The study confirmed sunitinib is an efficacious and safe treatment
option in progressive, locally advanced and/or metastatic, well-
differentiated, unresectable pNETs.
The Efficacy and Safety of Sunitinib in Patients With Advanced
Well‑Differentiated Pancreatic Neuroendocrine Tumors: Focus on Response Rate
E Raymond1
, MH Kulke2
, S Qin3
, X Yu4
, M Schenker5
, A Cubillo6
, W Lou7
, J Tomasek8
, E Thiis-Evensen9
, K Fernandez10
, B Rosbrook11
, N Fazio12
1
Paris Saint-Joseph Hospital Group, Paris, France; 2
Dana-Farber Cancer Institute, Boston, MA, USA; 3
PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4
Fudan University Shanghai Cancer Center, Shanghai, China; 5
Centrul de
Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 6
Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 7
Zhongshan Hospital, Fudan University, Shanghai, China; 8
Masarykuv
onkologicky ustav/Klinika komplexní onkologické péče, Brno, Czech Republic; 9
Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway;
10
Pfizer Inc, Cambridge, MA, USA; 11
Pfizer Inc, San Diego, CA, USA; 12
IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy
REFERENCES
1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.
2. Raymond E, et al. N Engl J Med 2011;364:501-13.
3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print].
4. Sutent®
(sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.
ACKNOWLEDGMENTS
We thank the participating patients and their families, as well as the global network of research nurses, trial
coordinators, and operations staff for their contributions, and investigators who participated in this trial, including:
M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane
(Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing
support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientific Solutions, and
was funded by Pfizer. Previously presented in part at the 2017 American Society of Clinical Oncology Gastrointestinal
Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA
For information on this poster, contact Eric Raymond, eraymond@hpsj.fr
Copyright © 2017
INTRODUCTION
•• Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an
estimated 53,070 new cases of pancreatic cancers expected in the US in
2016, pNETs account for fewer than 5%.1
•• Due to their relatively indolent nature, the majority of patients are
diagnosed with metastatic pNETs, for whom treatment options are
limited.
•• pNETs are highly vascularized tumors; aberrant expression of vascular
endothelial growth factor (VEGF) and its receptors, which play vital roles
in tumor angiogenesis, has been observed.
•• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis,
showed a significant increase in progression-free survival (PFS) over
placebo in well-differentiated, advanced and/or metastatic pNETs in a
pivotal phase III clinical trial (ClinicalTrials.gov NCT00428597).2
•• The trial was terminated early after more-serious adverse events (AEs) and
deaths were observed in the placebo arm and a difference in PFS favored
the sunitinib arm (hazard ratio [HR] 0.42; 95% confidence interval [CI],
0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).
–– The median (95% CI) 5-year overall survival (OS) was 38.6 (25.6–56.4)
months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR 0.73;
95% CI, 0.50–1.06; P=0.094), with 69% of placebo patients having
crossed over to sunitinib.3
•• In 2010 and 2011, sunitinib was approved by the European Medicines
Agency and US Food and Drug Administration (FDA), respectively, for the
treatment of patients with progressive, locally advanced and/or metastatic,
well-differentiated, unresectable pNETs.4
OBJECTIVES
•• This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was
conducted as post-approval commitments to the FDA and other
regulatory agencies to confirm the efficacy and safety of sunitinib in
advanced and/or metastatic, well-differentiated, unresectable pNETs.
METHODS
Study Design
•• This multinational, single-arm, open-label, phase IV clinical trial is ongoing.
•• The primary endpoint is investigator-assessed PFS per the Response
Evaluation Criteria in Solid Tumors (RECIST) v1.0.
•• Secondary endpoints include PFS assessed by the independent radiologic
review and per Choi criteria, time to tumor progression (TTP), objective
response rate (ORR), OS, and safety.
Key Eligibility Criteria
•• Histologically or cytologically confirmed, well-differentiated, unresectable or
metastatic pNETs with documented progression within 12 months of study
enrollment.
•• Not amenable to surgery, radiation, or combined modality therapy with
curative intent.
•• Presence of ≥1 measurable target lesion per RECIST v1.0.
•• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
•• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100
mmHg despite medical therapy).
•• No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.
Treatment and Assessments
•• Patients received 37.5 mg sunitinib orally once a day on a continuous daily
dosing regimen.
–– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks
of treatment initiation in patients without treatment response who
experienced only grade 1 or lower nonhematologic or grade 2 or lower
hematologic treatment-related AEs.
–– Dose could be temporarily interrupted or reduced to 25 mg daily to
manage severe toxicity.
•• Somatostatin analogs for control of symptoms were permitted at the
investigator’s discretion.
•• Radiologic tumor assessments were conducted at screening, Cycle 2
Day 1, Cycle 3 Day 1, and every 2 cycles thereafter; tumor responses were
evaluated per RECIST v1.0 criteria.
•• Safety was monitored throughout the study and AEs were graded according
to the National Cancer Institute Common Terminology Criteria for Adverse
Events v3.0.
Statistical Analyses
•• More than 80 patients were to be enrolled: 40 treatment-naïve (defined
as those who never received systemic antitumor therapy; somatostatin
analogs for symptomatic control were allowed) and 40 previously treated
patients.
•• Median PFS and 95% CI were estimated using the Kaplan–Meier method
for the entire population as well as separately for treatment-naïve and
previously treated patients.
•• Descriptive statistics were used to summarize other parameters.
RESULTS
Patients
•• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously
treated) were enrolled at 25 centers in 15 countries (Figure 1).
•• Patient demographics and baseline characteristics are summarized in
Table 1.
•• More than half (n=64/106, 60.4%) of patients had a nonfunctioning tumor
and 17.9% had a functioning tumor (unknown for 21.7% of patients).
Figure 1: Trial Profile
123 patients screened
106 patients enrolled
61 txt-naïve patients treated 45 previously treated patients treated
39 previously treated patients discontinued txt
23 Objective progression/relapse
8 Adverse events
1 Refusal of txt for reason other than AE
2 Global health deterioration
1 Death
4 Other
43 txt-naïve patients discontinued txt
26 Objective progression/relapse
6 Adverse events
4 Refusal of txt for reason other than AE
2 Global health deterioration
1 Death
4 Other
Efficacy analysis: 61 txt-naïve patients
Safety analysis: 61 txt-naïve patients
45 previously treated patients
45 previously treated patients
AE=adverse event; txt=treatment
•• In regard to prior locoregional treatment, 18.9% of patients had
trans-arterial chemoembolization; radiofrequency ablation (3.8%);
or trans-arterial embolization, percutaneous injections, or microwave
ablation (2.8% each).
•• Median (range) treatment duration in the total population was 11.7 months
(0.2–40.3): 12.2 months (0.2–35.9) in treatment-naïve vs 10.2 months
(0.5–40.3) in previously treated patients.
Efficacy
•• Median (95% CI) PFS as assessed by investigators was 13.2 months
(10.9–16.7); median (95% CI) PFS was similar in treatment-naïve and
previously treated patients (13.2 months [7.4–16.8] and 13.0 months
[9.2–20.4], respectively).
•• Median (95% CI) PFS per Choi criteria was 18.7 months (5.6–not estimable)
and 16.5 months (7.4–22.9) in treatment‑naïve and previously treated
patients, respectively (Figure 2).
•• Median (95% CI) PFS as assessed by independent radiological review
was 11.1 months (7.4–16.6), in treatment-naive patients 11.1 months
(5.5–16.7), and in previously treated patients 9.5 months (7.4–18.4).
–– 7 patients were censored due to lack of adequate baseline assessments.
Table 1: Demographics and Patient Baseline Characteristics
Characteristics
Treatment-Naïve
n=61
Previously Treated
n=45
Total
N=106
Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)
Gender, n (%)
Male 30 (49.2) 33 (73.3) 63 (59.4)
Female 31 (50.8) 12 (26.7) 43 (40.6)
Race, n (%)
White 32 (52.5) 35 (77.8) 67 (63.2)
Black 2 (3.3) 0 2 (1.9)
Asian 27 (44.3) 10 (22.2) 37 (34.9)
ECOG PS, n (%)
0 39 (63.9) 29 (64.4) 68 (64.2)
1 22 (36.1) 16 (35.6) 38 (35.8)
No. of involved disease sites,* n (%)
1 24 (39.3) 9 (20.0) 33 (31.1)
2 19 (31.1) 22 (48.9) 41 (38.7)
3 11 (18.0) 8 (17.8) 19 (17.9)
4 3 (4.9) 3 (6.7) 6 (5.7)
>4 4 (6.6) 3 (6.7) 7 (6.6)
Tumor site,* n (%)
Liver 57 (93.4) 41 (91.1) 98 (92.5)
Pancreas 22 (36.1) 25 (55.6) 47 (44.3)
Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4)
Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9)
Lung 3 (4.9) 3 (6.7) 6 (5.7)
Other 10 (16.4) 10 (22.2) 20 (18.9)
Any prior systemic
chemotherapy, n (%)
0 45 (100) 45 (42.5)
Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)
Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)
* Included both target and nontarget sites; sites with multiple lesions were counted once.
ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs
Figure 2: Kaplan–Meier Estimates of PFS Based on the Independent Third-Party
Radiology According to Choi Criteria PFS in Treatment-Naïve and Previously Treated
Patients With pNETs
PFSDistributionFunction
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 5 10 15 20 25
Time (Months)
No. at risk:
Treatment-naïve
Previously treated
61
45
29
25
22
17
11
11
6
8
4
5
1
4
0
2
0
0
0
0
30 35 40 45
Treatment-naïve 61 25 18.7 (5.6–NE)
Previously treated 45 24 16.5 (7.4–22.9)
n Events mPFS (95% CI), mo
CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; NE=not estimable;
pNET=pancreatic neuroendocrine tumor
•• ORR (95% CI) was 24.5% (16.7–33.8) according to the investigator
assessment.
•• The ORR (95% CI) per Choi criteria was higher than the ORR per RECIST:
52.5% (39.3–65.4) and 55.6% (40.0–70.4) in treatment-naïve and
previously treated patients, respectively (Table 2).
••
Table 2: Best Observed Response Based on Independent Third-Party Radiology
According to Choi Criteria in Treatment‑Naïve and Previously Treated Patients
With pNETs
Treatment-Naïve
n=61
Previously Treated
n=45
Best overall response, n (%)
Complete response 0 1 (2.2)
Partial response 32 (52.5) 24 (53.3)
Stable disease 12 (19.7) 17 (37.8)
Progressive disease 9 (14.8) 2 (4.4)
Indeterminate 8 (13.1) 1 (2.2)
ORR,* n (%) 32 (52.5) 25 (55.6)
95% CI 39.3–65.4 40.0–70.4
* Complete response + partial response.
CI=confidence interval; ORR=objective response rate; pNET=pancreatic neuroendocrine tumor; RECIST=Response Evaluation Criteria in
Solid Tumors
Median (95% CI) TTP was 14.5 months (11.0–16.7); median (95% CI) TTP
in treatment-naïve and previously treated patients was similar
(14.8 [7.5–16.8] and 14.5 [9.2–20.4] months, respectively).
–– According to the Choi criteria, the median (95% CI) TTP was 18.7 months
(5.6–not estimable) for treatment-naïve patients and 16.7 months
(7.4–30.9) for previously treated patients.
•• OS data were not mature at the time of data cutoff date (March 19, 2016);
29 (27.4%) patients had died and median (95% CI) OS was 37.8 months
(33.0–not estimable).
Safety
•• Most-common treatment-emergent, all-grade AEs experienced by all patients
treated with sunitinib included neutropenia, diarrhea, and leukopenia
(Table 3).
–– No major differences were observed in the incidence of AEs reported by
treatment-naïve vs previously treated patients, except dyspepsia, nausea,
and neutropenia.
•• Percentage of treatment-naïve and previously treated patients who
experienced Grade 3 or 4 AEs was comparable; serious AEs were also
comparable: 24.6% (n=15) vs 24.4% (n=11), respectively.
•• 15 (24.6%) treatment-naïve and 5 (11.1%) previously treated patients had
sunitinib dose reductions due to AEs; 8 (13.1%) and 10 (22.2%) patients,
respectively, discontinued treatment due to AEs.
Table 3: Treatment-Emergent, All-Causality Adverse Events
Adverse Events,* n (%)
Treatment-Naïve
n=61
Previously Treated
n=45
Total
N=106
All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)
Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)
Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)
Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)
Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)
Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)
Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)
Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)
Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)
Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)
Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)
Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)
Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)
Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)
Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)
Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)
ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)
AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)
Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)
Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)
Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)
Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)
Adverse events are listed by highest to lowest % for Total/All Grades patients.
* Adverse events reported by ≥15% in any treatment group per MedDRA criteria.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities